Cerebral volume is unaffected after pre-eclampsia.

OBJECTIVES: Pre-eclampsia has been associated with cardiovascular, cerebrovascular and/or psychological complaints. Signs of altered brain morphology and more white-matter hyperintensities (WMHs) during and shortly after pre-eclampsia have been observed in some, but not all, studies. We compared volumes of cerebral structures and the number of WMHs between formerly pre-eclamptic women and those with normotensive gestational history and assessed the effect of age on brain volumes. METHODS: Structural 7-Tesla magnetic resonance imaging of the brain was performed in 59 formerly pre-eclamptic women (aged 37 ± 6 years, 0.5-16 years postpartum) and 20 women with a history of normotensive pregnancy (aged 39 ± 5 years, 1-18 years postpartum). Fazekas scores were obtained to assess WMH load. Volumes of the whole brain, gray and white matter, brain lobes, and ventricular and pericortical cerebrospinal fluid (CSF) spaces were calculated after semiautomatic segmentation. Group differences were analyzed using ANCOVA and Bayes factors. Results were adjusted for age, educational attainment, presence of current hypertension and total intracranial volume. The effect of age on cerebral volumes was analyzed using linear regression analysis. RESULTS: No changes in global and local brain volumes were observed between formerly pre-eclamptic and control women. Also, no difference in WMH load was observed. Independent of pre-eclamptic history, gray-matter volume significantly decreased with age, while ventricular and pericortical CSF space volumes significantly increased with age. CONCLUSIONS: Volumetric changes of the cerebrum are age-related but are independent of pre-eclamptic history in the first two decades after childbirth. No evidence of greater WMH load after pre-eclampsia was found. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Functional connectivity of limbic system and prefrontal cortex years after pre-eclampsia: 7-Tesla functional magnetic resonance imaging study.

OBJECTIVE: Pre-eclampsia is a vascular complication of pregnancy, associated with a long-term risk of cerebrovascular and mental disorders. We explored whether formerly pre-eclamptic women exhibit differences in functional brain organization, especially in regions that may explain the commonly reported emotional symptoms and cognitive complaints even years after the pregnancy. METHODS: Formerly pre-eclamptic women and control women with a history of normotensive pregnancy underwent structural and functional 7-Tesla magnetic resonance imaging scans. Using graph theoretical analysis, the efficiency and clustering coefficient of the functional brain network were investigated. The study included local analysis focusing on particular brain structures, such as the limbic system and the prefrontal cortex, and global analysis of the whole cerebrum. Univariable and multivariable linear regression was used to investigate the relationship between brain network-related graph measures and the group (formerly pre-eclamptic or control). RESULTS: A total of 17 control parous women and 55 women with a history of pre-eclampsia were recruited. The time intervals between the index pregnancy and recruitment were 8.0 and 5.6 years for the two groups, respectively. Compared with control women, formerly pre-eclamptic women had higher local efficiency in the prefrontal cortex (P = 0.048) and anterior cingulate cortex (P = 0.03) but lower local efficiency and local clustering coefficient in the amygdala (P = 0.004 and P = 0.02, respectively) and parahippocampal cortex (P = 0.007 and P = 0.008, respectively). No differences were found in the global functional brain organization. CONCLUSIONS: Compared to controls with a history of normotensive pregnancy, formerly pre-eclamptic women displayed a different local functional brain organization. These differences in functional connectivity, especially in the limbic regions and the prefrontal cortex, are in line with the psychological and cognitive complaints reported commonly by women with a history of pre-eclampsia. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Blood-brain barrier leakage years after pre-eclampsia: dynamic contrast-enhanced 7-Tesla MRI study.

OBJECTIVE: Pre-eclampsia is a hypertensive complication of pregnancy that is associated with an increased risk of long-term cardiovascular and cerebrovascular disorders. Although the underlying mechanism of persistent susceptibility to cerebral complications after pre-eclampsia remains largely unclear, impaired blood-brain barrier (BBB) integrity has been suggested to precede several cerebrovascular diseases. In this study, we aimed to investigate the integrity of the BBB years after pre-eclampsia. METHODS: This was an observational study of premenopausal formerly pre-eclamptic women and controls with a history of normotensive pregnancy who underwent cerebral magnetic resonance imaging (MRI) at ultra-high field (7 Tesla) to assess the integrity of the BBB. Permeability of the BBB was determined by assessing leakage rate and fractional leakage volume of the contrast agent gadobutrol using dynamic contrast-enhanced MRI. BBB leakage measures were determined for the whole brain and lobar white and gray matter. Multivariable analyses were performed, and odds ratios were calculated to compare women with and those without a history of pre-eclampsia, adjusting for potential confounding effects of age, hypertension status at MRI and Fazekas score. RESULTS: Twenty-two formerly pre-eclamptic women (mean age, 37.8 ± 5.4 years) and 13 control women with a history of normotensive pregnancy (mean age, 40.8 ± 5.5 years) were included in the study. The time since the index pregnancy was 6.6 ± 3.2 years in the pre-eclamptic group and 9.0 ± 3.7 years in controls. The leakage rate and fractional leakage volume were significantly higher in formerly pre-eclamptic women than in controls in the global white (P = 0.001) and gray (P = 0.02) matter. Regionally, the frontal (P = 0.04) and parietal (P = 0.009) cortical gray matter, and the frontal (P = 0.001), temporal (P < 0.05) and occipital (P = 0.007) white matter showed higher leakage rates in formerly pre-eclamptic women. The odds of a high leakage rate after pre-eclampsia were generally higher in white-matter regions than in gray-matter regions. CONCLUSION: This observational study demonstrates global impairment of the BBB years after a pre-eclamptic pregnancy, which could be an early marker of long-term cerebrovascular disorders. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Value of ultra-high field MRI in patients with suspected focal epilepsy and negative 3 T MRI (EpiUltraStudy): protocol for a prospective, longitudinal therapeutic study.

PURPOSE: Resective epilepsy surgery is a well-established, evidence-based treatment option in patients with drug-resistant focal epilepsy. A major predictive factor of good surgical outcome is visualization and delineation of a potential epileptogenic lesion by MRI. However, frequently, these lesions are subtle and may escape detection by conventional MRI (≤ 3 T). METHODS: We present the EpiUltraStudy protocol to address the hypothesis that application of ultra-high field (UHF) MRI increases the rate of detection of structural lesions and functional brain aberrances in patients with drug-resistant focal epilepsy who are candidates for resective epilepsy surgery. Additionally, therapeutic gain will be addressed, testing whether increased lesion detection and tailored resections result in higher rates of seizure freedom 1 year after epilepsy surgery. Sixty patients enroll the study according to the following inclusion criteria: aged ≥ 12 years, diagnosed with drug-resistant focal epilepsy with a suspected epileptogenic focus, negative conventional 3 T MRI during pre-surgical work-up. RESULTS: All patients will be evaluated by 7 T MRI; ten patients will undergo an additional 9.4 T MRI exam. Images will be evaluated independently by two neuroradiologists and a neurologist or neurosurgeon. Clinical and UHF MRI will be discussed in the multidisciplinary epilepsy surgery conference. Demographic and epilepsy characteristics, along with postoperative seizure outcome and histopathological evaluation, will be recorded. CONCLUSION: This protocol was reviewed and approved by the local Institutional Review Board and complies with the Declaration of Helsinki and principles of Good Clinical Practice. Results will be submitted to international peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: www.trialregister.nl : NTR7536.

Ultra-high field magnetic resonance imaging in human epilepsy: A systematic review.

RATIONALE: Resective epilepsy surgery is an evidence-based curative treatment option for patients with drug-resistant focal epilepsy. The major preoperative predictor of a good surgical outcome is detection of an epileptogenic lesion by magnetic resonance imaging (MRI). Application of ultra-high field (UHF) MRI, i.e. field strengths ≥ 7 Tesla (T), may increase the sensitivity to detect such a lesion. METHODS: A keyword search strategy was submitted to Pubmed, EMBASE, Cochrane Database and clinicaltrials.gov to select studies on UHF MRI in patients with epilepsy. Follow-up study selection and data extraction were performed following PRISMA guidelines. We focused on I) diagnostic gain of UHF- over conventional MRI, II) concordance of MRI-detected lesion, seizure onset zone and surgical decision-making, and III) postoperative histopathological diagnosis and seizure outcome. RESULTS: Sixteen observational cohort studies, all using 7T MRI were included. Diagnostic gain of 7T over conventional MRI ranged from 8% to 67%, with a pooled gain of 31%. Novel techniques to visualize pathological processes in epilepsy and lesion detection are discussed. Seizure freedom was achieved in 73% of operated patients; no seizure outcome comparison was made between 7T MRI positive, 7T negative and 3T positive patients. 7T could influence surgical decision-making, with high concordance of lesion and seizure onset zone. Focal cortical dysplasia (54%), hippocampal sclerosis (12%) and gliosis (8.1%) were the most frequently diagnosed histopathological entities. SIGNIFICANCE: UHF MRI increases, yet variably, the sensitivity to detect an epileptogenic lesion, showing potential for use in clinical practice. It remains to be established whether this results in improved seizure outcome after surgical treatment. Prospective studies with larger cohorts of epilepsy patients, uniform scan and sequence protocols, and innovative post-processing technology are equally important as further increasing field strengths. Besides technical ameliorations, improved correlation of imaging features with clinical semiology, histopathology and clinical outcome has to be established.

Association of physical activity and sedentary time with structural brain networks-The Maastricht Study.

We assessed whether objectively measured low- and high-intensity physical activity (LPA and HPA) and sedentary time (ST) were associated with white matter connectivity, both throughout the whole brain and in brain regions involved in motor function. In the large population-based Maastricht Study (n = 1715, age 59.6 ± 8.1 (mean ± standard deviation) years, and 48% women), the amounts of LPA, HPA, and ST were objectively measured during 7 days by an activPAL accelerometer. In addition, using 3T structural and diffusion MRI, we calculated whole brain node degree and node degree of the basal ganglia and primary motor cortex. Multivariable linear regression analysis was performed, and we report standardized regression coefficients (stß) adjusted for age, sex, education level, wake time, diabetes status, BMI, office systolic blood pressure, antihypertensive medication, total-cholesterol-to-HDL-cholesterol ratio, lipid-modifying medication, alcohol use, smoking status, and history of cardiovascular disease. Lower HPA was associated with lower whole brain node degree after full adjustment (stß [95%CI] = - 0.062 [- 0.101, - 0.013]; p = 0.014), whereas lower LPA (stß [95%CI] = - 0.013 [- 0.061, 0.034]; p = 0.580) and higher ST (stß [95%CI] = - 0.030 [- 0.081, 0.021]; p = 0.250) was not. In addition, lower HPA was associated with lower node degree of the basal ganglia after full adjustment (stß [95%CI] = - 0.070 [- 0.121, - 0.018]; p = 0.009). Objectively measured lower HPA, but not lower LPA and higher ST, was associated with lower whole brain node degree and node degree in specific brain regions highly specialized in motor function. Further research is needed to establish whether more HPA may preserve structural brain connectivity.

The TRACK-PD study: protocol of a longitudinal ultra-high field imaging study in Parkinson's disease.

BACKGROUND: The diagnosis of Parkinson's Disease (PD) remains a challenge and is currently based on the assessment of clinical symptoms. PD is also a heterogeneous disease with great variability in symptoms, disease course, and response to therapy. There is a general need for a better understanding of this heterogeneity and the interlinked long-term changes in brain function and structure in PD. Over the past years there is increasing interest in the value of new paradigms in Magnetic Resonance Imaging (MRI) and the potential of ultra-high field strength imaging in the diagnostic work-up of PD. With this multimodal 7 T MRI study, our objectives are: 1) To identify distinctive MRI characteristics in PD patients and to create a diagnostic tool based on these differences. 2) To correlate MRI characteristics to clinical phenotype, genetics and progression of symptoms. 3) To detect future imaging biomarkers for disease progression that could be valuable for the evaluation of new therapies. METHODS: The TRACK-PD study is a longitudinal observational study in a cohort of 130 recently diagnosed (≤ 3 years after diagnosis) PD patients and 60 age-matched healthy controls (HC). A 7 T MRI of the brain will be performed at baseline and repeated after 2 and 4 years. Complete assessment of motor, cognitive, neuropsychiatric and autonomic symptoms will be performed at baseline and follow-up visits with wearable sensors, validated questionnaires and rating scales. At baseline a blood DNA sample will also be collected. DISCUSSION: This is the first longitudinal, observational, 7 T MRI study in PD patients. With this study, an important contribution can be made to the improvement of the current diagnostic process in PD. Moreover, this study will be able to provide valuable information related to the different clinical phenotypes of PD and their correlating MRI characteristics. The long-term aim of this study is to better understand PD and develop new biomarkers for disease progression which may help new therapy development. Eventually, this may lead to predictive models for individual PD patients and towards personalized medicine in the future. TRIAL REGISTRATION: Dutch Trial Register, NL7558 . Registered March 11, 2019.

Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin.

There is growing interest in the therapeutic utility of psychedelic substances, like psilocybin, for disorders characterized by distortions of the self-experience, like depression. Accumulating preclinical evidence emphasizes the role of the glutamate system in the acute action of the drug on brain and behavior; however this has never been tested in humans. Following a double-blind, placebo-controlled, parallel group design, we utilized an ultra-high field multimodal brain imaging approach and demonstrated that psilocybin (0.17 mg/kg) induced region-dependent alterations in glutamate, which predicted distortions in the subjective experience of one's self (ego dissolution). Whereas higher levels of medial prefrontal cortical glutamate were associated with negatively experienced ego dissolution, lower levels in hippocampal glutamate were associated with positively experienced ego dissolution. Such findings provide further insights into the underlying neurobiological mechanisms of the psychedelic, as well as the baseline, state. Importantly, they may also provide a neurochemical basis for therapeutic effects as witnessed in ongoing clinical trials.

Revealing structural evolution occurring from photo-initiated polymer network formation.

Photopolymerization is a key enabling technology offering spatial and temporal control to allow for future functional materials to be made to meet societal needs. However, gaining access to robust experimental techniques to describe the evolution of nanoscale morphology in photo-initiated polymeric systems has proven so far to be a challenging task. Here, we show that these physical transformations can be monitored and quantified at the nanoscale in situ and in real-time. It is demonstrated that the initial structural features of the liquid precursors significantly affect the final morphology and the physical properties of the resulting solid via the occurrence of local heterogeneities in the molecular mobility during the curing transformation. We have made visible how local physical arrestings in the liquid, associated with both cross-linking and vitrification, determine the length scale of the local heterogeneities forming upon curing, found to be in the 10-200 nm range.

Optimal Detection of Subtle Gadolinium Leakage in CSF with Heavily T2-Weighted Fluid-Attenuated Inversion Recovery Imaging.

Pericortical enhancement on postcontrast FLAIR images is a marker for subtle leptomeningeal blood-brain barrier leakage. We explored the optimal FLAIR sequence parameters for the detection of low gadolinium concentrations within the CSF. On the basis of phantom experiments and human in vivo data, we showed that detection of subtle pericortical enhancement can be facilitated by using a relatively long TE. Future studies should choose their FLAIR sequence parameters carefully when assessing pericortical enhancement due to subtle blood-brain barrier leakage.

Abnormal Blood Oxygen Level-Dependent Fluctuations in Focal Cortical Dysplasia and the Perilesional Zone: Initial Findings.

BACKGROUND AND PURPOSE: Focal cortical dysplasia is a common cause of intractable epilepsy for which neurosurgery is an option. Delineations of a focal cortical dysplasia lesion on structural brain images may not necessarily reflect the functional borders of normal tissue. Our objective was to determine whether abnormalities in spontaneous blood oxygen level-dependent fluctuations arise in focal cortical dysplasia lesions and proximal regions. MATERIALS AND METHODS: Fourteen patients with focal cortical dysplasia-related epilepsy and 16 healthy controls underwent structural and resting-state functional MR imaging. Three known blood oxygen level-dependent measures were determined, including the fractional amplitude of low-frequency fluctuations, regional homogeneity, and wavelet entropy. These measures were evaluated in the lesion and perilesional zone and normalized to the contralateral cortex of patients with focal cortical dysplasia and healthy controls. RESULTS: Patients showed significantly decreased fractional amplitude of low-frequency fluctuations and increased wavelet entropy in the focal cortical dysplasia lesion and the perilesional zone (≤2 cm) relative to the contralateral homotopic cortex and the same regions in healthy controls. Regional homogeneity was significantly increased in the focal cortical dysplasia lesion compared with the contralateral homotopic cortex and healthy controls. CONCLUSIONS: Abnormalities in spontaneous blood oxygen level-dependent fluctuations were seen up to 2 cm distant from the radiologically visible boundary. It was demonstrated that functional boundaries go beyond structural boundaries of focal cortical dysplasia lesions. Validation is required to reveal whether this information is valuable for surgical planning and outcome evaluation of focal cortical dysplasia lesions and comparing current results with electrophysiologic analysis.

Interaction between blood-brain barrier and glymphatic system in solute clearance.

Neurovascular pathology concurs with protein accumulation, as the brain vasculature is important for waste clearance. Interstitial solutes, such as amyloid-ß, were previously thought to be primarily cleared from the brain by blood-brain barrier transport. Recently, the glymphatic system was discovered, in which cerebrospinal fluid is exchanged with interstitial fluid, facilitated by the aquaporin-4 water channels on the astroglial endfeet. Glymphatic flow can clear solutes from the interstitial space. Blood-brain barrier transport and glymphatic clearance likely serve complementary roles with partially overlapping mechanisms providing a well-conditioned neuronal environment. Disruption of these mechanisms can lead to protein accumulation and may initiate neurodegenerative disorders, for instance amyloid-ß accumulation and Alzheimer's disease. Although both mechanisms seem to have a similar purpose, their interaction has not been clearly discussed previously. This review focusses on this interaction in healthy and pathological conditions. Future health initiatives improving waste clearance might delay or even prevent onset of neurodegenerative disorders. Defining glymphatic flow kinetics using imaging may become an alternative way to identify those at risk of Alzheimer's disease.

On the Reproducibility of Inversion Recovery Intravoxel Incoherent Motion Imaging in Cerebrovascular Disease.

BACKGROUND AND PURPOSE: Intravoxel incoherent motion imaging can measure both microvascular and parenchymal abnormalities simultaneously. The contamination of CSF signal can be suppressed using inversion recovery preparation. The clinical feasibility of inversion recovery-intravoxel incoherent motion imaging was investigated in patients with cerebrovascular disease by studying its reproducibility. MATERIALS AND METHODS: Sixteen patients with cerebrovascular disease (66 ± 8 years of age) underwent inversion recovery-intravoxel incoherent motion imaging twice. The reproducibility of the perfusion volume fraction and parenchymal diffusivity was calculated with the coefficient of variation, intraclass correlation coefficient, and the repeatability coefficient. ROIs included the normal-appearing white matter, cortex, deep gray matter, white matter hyperintensities, and vascular lesions. RESULTS: Values for the perfusion volume fraction ranged from 2.42 to 3.97 ×10-2 and for parenchymal diffusivity from 7.20 to 9.11 × 10-4 mm2/s, with higher values found in the white matter hyperintensities and vascular lesions. Coefficients of variation were <3.70% in normal-appearing tissue and <9.15% for lesions. Intraclass correlation coefficients were good to excellent, showing values ranging from 0.82 to 0.99 in all ROIs, except the deep gray matter and cortex, with intraclass correlation coefficients of 0.66 and 0.54, respectively. The repeatability coefficients ranged from 0.15 to 0.96 × 10-2 and 0.10 to 0.37 × 10-4 mm2/s for perfusion volume fraction and parenchymal diffusivity, respectively. CONCLUSIONS: Good reproducibility of inversion recovery-intravoxel incoherent motion imaging was observed with low coefficients of variation and high intraclass correlation coefficients in normal-appearing tissue and lesion areas in cerebrovascular disease. Good reproducibility of inversion recovery-intravoxel incoherent motion imaging in cerebrovascular disease is feasible in monitoring disease progression or treatment responses in the clinic.

Pericortical Enhancement on Delayed Postgadolinium Fluid-Attenuated Inversion Recovery Images in Normal Aging, Mild Cognitive Impairment, and Alzheimer Disease.

BACKGROUND AND PURPOSE: Breakdown of BBB integrity occurs in dementia and may lead to neurodegeneration and cognitive decline. We assessed whether extravasation of gadolinium chelate could be visualized on delayed postcontrast FLAIR images in older individuals with and without cognitive impairment. MATERIALS AND METHODS: Seventy-four individuals participated in this study (15 with Alzheimer disease, 33 with mild cognitive impairment, and 26 with normal cognition). We assessed the appearance of pericortical enhancement after contrast administration, MR imaging markers of cerebrovascular damage, and medial temporal lobe atrophy. Three participants who were positive for pericortical enhancement (1 with normal cognition and 2 with mild cognitive impairment) were followed up for approximately 2 years. In vitro experiments with a range of gadolinium concentrations served to elucidate the mechanisms underlying the postcontrast FLAIR signals. RESULTS: Postcontrast pericortical enhancement was observed in 21 participants (28%), including 6 individuals with Alzheimer disease (40%), 10 with mild cognitive impairment (30%), and 5 with normal cognition (19%). Pericortical enhancement was positively associated with age (P < .02) and ischemic stroke (P < .05), but not with cognitive status (P = .3). Foci with enhanced signal remained stable across time in all follow-up cases. The in vitro measurements confirmed that FLAIR imaging is highly sensitive for the detection of low gadolinium concentrations in CSF, but not in cerebral tissue. CONCLUSIONS: Postcontrast pericortical enhancement on FLAIR images occurs in older individuals with normal cognition, mild cognitive impairment, and dementia. It may represent chronic focal superficial BBB leakage. Future longitudinal studies are needed to determine its clinical significance.

Altered Hippocampal White Matter Connectivity in Type 2 Diabetes Mellitus and Memory Decrements.

Type 2 diabetes mellitus is associated with cognitive decrements. Specifically affected cognitive domains are learning and memory, for which the hippocampus plays an essential role. The pathophysiological mechanism remains to be revealed. The present study examined whether local hippocampal microstructure and white matter connectivity are related to type 2 diabetes and memory performance. Forty participants with type 2 diabetes and 38 participants without type 2 diabetes underwent detailed cognitive assessment and 3-Tesla diffusion magnetic resonance imaging (MRI). Diffusion MRI was performed to assess microstructure (fractional anisotropy and mean diffusivity) and white matter connectivity (tract volume) of the hippocampus, which were compared between participants with and without type 2 diabetes. No differences in hippocampal microstructure were observed. Participants with type 2 diabetes had fewer white matter connections between the hippocampus and frontal lobe (P = 0.017). Participants who scored lower on memory function, regardless of type 2 diabetes, had fewer white matter connections between the hippocampus and temporal lobe (P = 0.017). Taken together, type 2 diabetes and memory decrements appear to be associated with altered hippocampal white matter connectivity.

Cognitive effects of lacosamide as adjunctive therapy in refractory epilepsy.

BACKGROUND: Lacosamide (LCM) is a novel antiepileptic drug (AED) with potential benefit as adjunctive treatment in patients with partial-onset seizures. As yet, limited information on cognitive effects of LCM is available, especially in real-life settings. AIMS: In this open clinical prospective study, the cognitive effects of LCM were evaluated when used as adjunctive antiepileptic therapy in patients with refractory epilepsy. METHODS: We included 33 patients aged between 16 and 74 years (mean: 37 years). All patients had a localization-related epilepsy. Patients were assessed at baseline before starting LCM treatment and during follow-up when the optimal clinical dose was achieved. MATERIALS: Subjective complaints were evaluated using the SIDAED; effects on cognition were evaluated using the computerized visual searching task (CVST). RESULTS: The CVST showed significant faster information processing reaction times at the second evaluation (P = 0.013), which was not correlated with seizure control, type of epilepsy, age, gender, drug load, number of concomitant drugs, dose or duration of LCM treatment. On the SIDAED, patients complained more about their cognitive function at the second evaluation (P = 0.005). For the SIDAED, a positive correlation at follow-up was found between the total severity score and higher age (r = 0.375, P = 0.031), but not with epilepsy factors or treatment characteristics. DISCUSSION/CONLUSION: Screening of the cognitive effects of LCM showed that LCM does not have negative effects on information processing speed. As this is the most sensitive function for cognitive side effects of AEDs, LCM does not seem to induce the common negative cognitive effects. Remarkably, patients complained more, especially about their cognitive function, which is possible the 'doing better, feeling worse phenomenon'.

Aetiology of cognitive impairment in children with frontal lobe epilepsy.

OBJECTIVES: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its aetiology is unknown. MRI scans often reveal no structural brain abnormalities that could explain the cognitive impairment. This does not exclude more subtle morphological abnormalities that can only be detected by automated morphometric techniques. AIMS: With these techniques, we investigate the relationship between cortical brain morphology and cognitive functioning in a cohort of children with FLE and healthy controls. MATERIALS AND METHODS: Thirty-four children aged 8-13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural brain MRI. Patients were grouped as cognitively impaired or unimpaired. Intracranial volume, white matter volume, lobular cortical volume, cortical thickness and volumes of cortex structures were compared between patients and controls, and potential correlations with cognitive status were determined. RESULTS: The group of cognitively impaired children with FLE had significantly smaller left temporal cortex volumes, specifically middle temporal grey matter volume and entorhinal cortex thickness. In addition, cognitively impaired children with FLE had smaller volumes of structures in the left and right frontal cortex, right temporal cortex and the left subcortical area. CONCLUSION: Cognitively impaired children with FLE have smaller volumes of various cortex structures within the frontal lobes and in extra-frontal regions, most notably temporal cortex volumes. These findings might well explain the broad scale of cognitive domains affected in children with FLE complicated by cognitive impairment and highlight that FLE impacts on areas beyond the frontal lobe.

Pediatric frontal lobe epilepsy: white matter abnormalities and cognitive impairment.

OBJECTIVES: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE). Its etiology remains unknown. With diffusion tensor imaging, we have studied cerebral white matter properties and associations with cognitive functioning in children with FLE and healthy controls. METHODS: Thirty children aged 8-13 years with FLE of unknown cause and 39 healthy age-matched controls underwent neuropsychological assessment, structural and diffusion-weighted brain MRI. Patients were grouped as cognitively impaired or unimpaired, and their white matter diffusion properties were compared with the controls. RESULTS: Children with FLE had reduced apparent diffusion coefficients in various posteriorly located tract bundles, a reduced fractional anisotropy (FA) of the white matter tract between the right frontal and right occipital lobe, and smaller volumes of several collections of interlobar bundle tracts, compared with controls. The cognitively impaired patient group demonstrated significant increases in FA of the white matter of both occipital lobes, a reduced FA of white matter tract bundles between the right frontal and both left occipital lobe and subcortical white matter area, and smaller volumes of two collections of tract bundles connecting the frontal lobe with the temporal and parietal lobes, compared with controls. CONCLUSIONS: Children with FLE had white matter abnormalities mainly in posterior brain regions, not confined to the area of the seizure focus. Cognitively impaired children with FLE showed the most pronounced white matter abnormalities. These possibly reflect disturbed maturation and might be part of the etiology of the cognitive impairment.

Abnormal modular organization of functional networks in cognitively impaired children with frontal lobe epilepsy.

Many children with frontal lobe epilepsy (FLE) have significant cognitive comorbidity, for which the underlying mechanism has not yet been unraveled, but is likely related to disturbed cerebral network integrity. Using resting-state fMRI, we investigated whether cerebral network characteristics are associated with epilepsy and cognitive comorbidity. We included 37 children with FLE and 41 healthy age-matched controls. Cognitive performance was determined by means of a computerized visual searching task. A connectivity matrix for 82 cortical and subcortical brain regions was generated for each subject by calculating the inter-regional correlation of the fMRI time signals. From the connectivity matrix, graph metrics were calculated and the anatomical configuration of aberrant connections and modular organization was investigated. Both patients and controls displayed efficiently organized networks. However, FLE patients displayed a higher modularity, implying that subnetworks are less interconnected. Impaired cognition was associated with higher modularity scores and abnormal modular organization of the brain, which was mainly expressed as a decrease in long-range and an increase in interhemispheric connectivity in patients. We showed that network modularity analysis provides a sensitive marker for cognitive impairment in FLE and suggest that abnormally interconnected functional subnetworks of the brain might underlie the cognitive problems in children with FLE.

Loss of network efficiency associated with cognitive decline in chronic epilepsy.

OBJECTIVE: To study the relation between possibly altered whole brain topology and intellectual decline in chronic epilepsy, a combined study of neurocognitive assessment and graph theoretical network analysis of fMRI was performed. METHODS: Forty-one adult patients with cryptogenic localization-related epilepsy and 23 healthy controls underwent an intelligence test and fMRI with a silent-word generation paradigm. A set of undirected graphs was constructed by cross-correlating the signal time series of 893 cortical and subcortical regions. Possible changes in cerebral network efficiency were assessed by performing graph theoretical network analysis. RESULTS: Healthy subjects displayed efficient small world properties, characterized by high clustering and short path lengths. On the contrary, in patients with epilepsy a disruption of both local segregation and global integration was found. An association of more pronounced intellectual decline with more disturbed local segregation was observed in the patient group. The effect of antiepileptic drug use on cognitive decline was mediated by decreased clustering. CONCLUSIONS: These findings support the hypothesis that chronic localization-related epilepsy causes cognitive deficits by inducing global cerebral network changes instead of a localized disruption only. Whether this is the result of epilepsy per se or the use of antiepileptic drugs remains to be elucidated. For application in clinical practice, future studies should address the relevance of altered cerebral network topology in prediction of cognitive deficits and monitoring of therapeutic interventions.